An autoantibody is an antibody manufactured by an individual's immune system that is directed against an antigen of the individual's own proteins. Antibodies are normally produced in response to a foreign protein or substance within the body, typically a pathogen, which is an infectious organism. Normally, the immune system is able to recognize and ignore the body's own cells and not overreact to non-threatening substances in the environment, such as foods. Sometimes, however, the immune system ceases to recognize one or more of the body's normal constituents as “self”, leading to production of autoantibodies. These autoantibodies attack the body's own cells, tissues, and/or organs, causing inflammation and damage.
Serum autoantibodies have been implicated in a wide variety of neurological diseases and syndromes. Neuron-binding autoantibodies have been detected in sera from individuals exhibiting obsessive compulsive disorder, Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (“PANDAS”), and Hashimoto's encephalopathy. Schizophrenia has also been linked to the appearance of autoantibodies, including several directed against neuronal surface receptors. Systemic lupus erythematosus (“SLE”), known to be caused by antinuclear antibodies, appears to have cognitive and memory loss components consistent with the presence of a subset of anti-DNA antibodies that cross-react with the N-methyl-D-aspartate receptor (“NMDAR”). Also, brain-reactive antibodies in mothers of autistic children elicit behavioral abnormalities in progeny when administered to pregnant mammals.
Moreover, among neurodegenerative diseases, autoantibodies have been found in Parkinson's disease, Autism spectrum disorders, amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic peripheral neuropathy, optic neuritis, vascular dementia, and Alzheimers disease (“AD”). In the case of AD, there have been numerous reports of patients having high titers of autoantibodies to both non-brain and brain-associated targets, including neuron-binding autoantibodies. Moreover, several specific autoantibody targets have been identified, including aldolase, heavy neurofilament subunit, histone, tubulin, glial fibrillary acid protein, and S-100.
Alzheimer's disease (AD) is a progressive and devastating neurodegenerative disorder of the elderly that is highlighted by a dramatic reduction of memory and cognition and linked to loss of neurons and synapses (Selkoe (2002) Science 298, 789-91). Additional key pathological features include the deposition of amyloid beta (Aβ), especially the 42-amino acid peptide (Aβ42), within neurons, amyloid plaques and in the walls of brain blood vessels, as well as the appearance of neurofibrillary tangles, glial activation and widespread inflammation (Schwab et al. (2008) J Alzheimers Dis 13, 359-69; Thal et al. (2008) Acta Neuropathol 115, 599-609; Weisman et al. (2006) Vitam Horm 74, 505-30). Aβ42 deposition within neurons is initiated early in the course of the disease, precedes amyloid plaque and tangle formation, and temporally and spatially coincides with loss of synapses in human AD and transgenic mouse brains (D'Andrea et al. (2001) Histopathology 38, 120-134; Nagele et al. (2002) J Neurosci 110, 199-211; Gouras et al. (2000) Am J Patho. 156, 15-20). This has led to the proposal that the gradual growth of Aβ deposits may progressively impair the ability of neurons to support their extensive dendritic arbors, thereby contributing to early synaptic loss that eventually becomes apparent through telltale symptoms.
Studies have reported the presence of immunoglobulin (Ig)-immunopositive neurons in histological sections of post-mortem AD brains, which were only rarely observed in comparable brain regions of non-demented, age-matched controls (Stein et al. (2002) J Neuropathol Exp Neurol 61, 1100-8; Bouras et al. (2005) Brain Res Brain Res Rev 48, 477-87; D'Andrea (2003) Brain Res Brain Res Rev 982, 19-30). The presence of specific brain-reactive autoantibodies in the serum of AD patients has also been reported. (Bouras et al. (2005) Brain Res Brain Res Rev 48, 477-87; Kulmala et al. (1987) Exp Aging Res 13, 67-72; Mecocci et al. (1993) Biol Psychiatry 34, 380-5; Mecocci et al. (1995) J Neuroimmunol 57, 165-70; Weksler et al. (2002) Exp Gerontol 37, 971-979).
Autism spectrum disorders (“ASDs”) are a group of disorders in brain development that includes autism, Asperger's syndrome, Rett's disorder, and childhood disintegrative disorder. ASDs are characterized by impairments in social behavior and communication that are usually expressed within the first 36 months of childhood (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (2000)). A substantial fraction (20-30%) of autism patients undergo a period of autistic regression during which they experience a loss of previously acquired milestones in language and behavioral skills (Fombonne (2003) JAMA 289, 87-89). Inexplicably, the prevalence of ASD has recently increased dramatically, a finding not due to improved diagnostics, but rather suggesting some environmental causal factor(s). ASDs now affect 1:150 children, and the etiology is largely unknown but likely to be multifactorial (Fombonne, 2003).
Neuropathological and neuroimaging studies of autistic patients have reported increased brain size and weight (Bailey et al. (1998) Psychol Med 25, 63-77; Kemper and Bauman (1998) Neurol Clinic 1, 175-87; Palmen et al. (2004) Brain 127, 2572-2583). Many studies of autistic brains have reported an overall reduction in neuron size and an increased neuron packing density, especially in the hippocampus, subiculum and amygdala (Kemper and Bauman, 1993).
ASDs have been linked to specific brain abnormalities. Neurological observations and neuroimaging studies have provided evidence that many brain regions can be affected in autism, including the cerebellum, cerebral cortex, amygdala, hippocampus, basal ganglia and the brain stem (Akshoomoff et al., 2002; Acosta and Pearl (2004) Semin Pediatr Neurol 11, 205-213). Cerebellar abnormalities are also common in ASD, hallmarked by a scarcity of Purkinje and granule cells (Courchesne et al., 2001).
Autoimmunity and autoantibodies are involved in the pathogenesis of ASDs (Ashwood et al. (2006) J Leukocyte Biol 80, 1-11; Wills et al. (2007) Ann N.Y. Acad Sci 1107, 79-91; Zimmerman et al. (2007) Brain Behav Immun 21, 351-357). The binding of autoantibodies to neurons can disrupt the normal pattern of neurodevelopment at critical stages. Autoantibodies reactive to the brain have been reported in autistic children, and several autoimmune factors including brain-specific autoantibodies, impaired lymphocyte function, abnormal cytokine regulation, and viral associations have been implicated (Singh and Rivas (2004) Neurosci Lett 355, 53-56). For example, Singh and Rivas (2004) have shown that the serum of autistic children contains brain-specific autoantibodies. In a study of 68 autistic children at 4-12 years of age, antibodies to the caudate nucleus, cerebral cortex and cerebellum were detected in 49%, 18% and 9%, respectively, of autistic children, but not in normal children. Another study has shown that children with Tourette syndrome possess anti-striatal antibodies, and influsion of these antibodies into the rat striatum caused neuronal dysfunction similar to Tourette syndrome (Hallet et al. (2000) J Neuroimmunol 111, 195-202). Other anti-brain antibodies have also been found in autistic patients, including antibodies to serotonin receptor, myelin basic protein, axon filament protein, cerebellar neurofilaments, nerve growth factor, brain endothelial proteins and antibodies directed against other unidentified brain proteins.
A strong link between the presence of anti-neuronal autoantibodies and neurological disease has been shown in children in cases following streptococcal infections, such as in obsessive compulsive disorder (OCD), Sydenham's chorea, Tourette syndrome, PANDAS, and paraneoplasia, and in elderly patients with SLE that show both cognitive and memory loss (Swedo et al. (1989) Am J Psychiatry 154, 110-2; Kalume et al. (2004) J Neurosci Res 77, 82-89; Tanaka et al. (2004) J Neurological Sci 217, 25-30). DeGeorgio et al. (2001) Nature Med 11, 1189-1193 and Kowal et al. (2004) Immunity 21, 179-188, report that a subset of anti-DNA antibodies in SLE patients cross-reacts with the NMDA (N-methyl-D-aspartate) subtype of glutamate receptors (NR2a and NR2b) by means of molecular mimicry and induces neuronal injury and death both in vivo and in vitro.